1. B cells
The response of an individual to tumor cells involves the reactions and counteractions mediated by both cellular and humoral arms of the immune system. Tumor cell growth may represent a disturbance in the equilibrium of the immune system that is pre-existing, and/or induced by the tumor cells themselves. However, most investigations to date have focused on the role of T cells in tumor immunity. The role of B cells in a tumor-bearing individual still remains unclear.
Previous studies have shown that lymph nodes regional to a primary tumor in cancer patients, and in in vivo experimental animal models of tumor development, can undergo a prominent expansion in the germinal centers (Eremin et al., 1980, Br. J. Cancer 41:62; Bertschmann et al., 1984, Br. J. Cancer 49:477-484). In lymph nodes, prominent expansion of immune cells includes B lymphocytes (B cells). The reason(s) for this observed B cell pro-liferative response remains unclear, and may be due to either activation and stimulation directly by tumor cells or tumor cell components, and/or indirectly by stimulation of T-helper cells which then activate and stimulate B cells. A recent study confirmed the increase in the number of B cells in lymph nodes regional to primary tumors (Ito et al., 1996, Immunobiol. 195:1-15). The number of B cells increase in the regional lymph nodes concomitantly with tumor development, and such B cells appear to be able to elicit anti-tumor immunity. In that regard, there are numerous reports that cancer patients have circulating antitumor antibodies (see, e.g., Carey et al., 1976, Proc. Natl. Acad. Sci. USA 73:3278-3282; Abe et al., 1989, Cancer Res. 80:271-276; Christensen et al., 1989, Int. J. Cancer 37:683-688).
However, unlike the pattern found in the lymph nodes, the percentage of B lymphocyte populations in the blood of cancer patients are similar to the values found in healthy controls (Eremin et al., 1976, Int. Archs Allergy appl. Immun. 52:277-290; Svennevig et al., 1979, Int. J. Cancer 23:626-631). Some studies report a lower mean percentage of circulating B lymphocytes in cancer patients as compared to the mean percentage in apparently normal individuals (Wood and Neff, 1978, J. Natl. Cancer Inst. 61:715-718). In these latter studies, the low values of circulating B lymphocytes were observed both in the absence of therapy, and in the presence of chemotherapy or radiation therapy; and further, could not be found to correlate with the stage of disease. More recently, the percentage of a specific subpopulation of B lymphocytes, identified as CD5+ and also known as B1 cells, appears to be slightly increased in the peripheral blood of cancer patients as compared to the values in healthy controls (Stein et al., 1991, Clin. Exp. Immunol. 85:418-23). It is noted that CD5+ B cells are a different cell subset than memory B cells (CD5-; Brown, 1992, Crit. Rev. Immunol. 11:395-417). While it appears that a humoral immune response towards tumor-associated antigens can be mounted in cancer patients, the role of the B cells in the host response to tumor, and any significance relative to the detection of B cells in the host response to tumor, remain poorly defined.
2. T cells
T cell subsets, mainly CD4+ cells and CD8+ cells, have been studied in individuals having solid, nonlymphoid tumor. In general, regional lymph nodes close to (e.g., draining) a primary solid, nonlymphoid tumor, and the nodes involved with metastases thereof, show a significant decrease of CD4+ T cells (see, e.g., Takemura et al., 1991, Cancer J. 4:244-248). As to peripheral blood values, it is a general observation that activated CD4+ T cells (CD4+ , HLA DR+) may be significantly higher in amounts in Stage I patients than that observed in healthy controls, but that the CD4+ subset becomes significantly decreased during advanced stages of malignancy. In patients with bladder cancer, the absolute number of CD11b+ CD8+ cells (suppressor T lymphocytes) in peripheral blood correlated inversely with histological grade. Additionally, there was a significantly lower absolute number of peripheral blood CD11b- CD8+ cells (cytotoxic T lymphocytes) in patients with invasive bladder cancer as compared to that in patients with superficial bladder cancer (see, e.g., Ono et al., 1996, Reg. Cancer Treat. 9:40-43). It has also been reported that radiation therapy for primary cancer results in reduced B lymphocytes and reduced T lymphocytes in proportion to their total lymphocyte population, so that their percentages remain unchanged.
3. Follicular dendritic cells
Dendritic cells are a population of antigen presenting cells that comprise multiple distinct subpopulations. The distinct subpopulations of dendritic cells include: (a) Langerhans cells found in the skin above the basal layer of proliferating keritinocytes (e.g., CD1a+); (b) interdigitating dendritic cells (CD40.sup.high, B7.1/CD80.sup.high, B7.2/CD86.sup.high); and follicular dendritic cells (DRC-1, KIM4+) (see, e.g., Liu and Arpin, 1997, Immunol. Rev. 156:111-126). Follicular dendritic cells (FDC) reside in germinal centers within lymphoid follicles of secondary lymphoid tissues. FDC have a distinctive ability to trap and retain unprocessed antigen, in the form of immune complexes, in a spacial arrangement for effective antigen presentation to B cells. Hence, FDC are the main antigen presenting cells to B cells in the germinal center, and play a major role in inducing B cell proliferation in lymph nodes. Precursors of FDC may be present in low numbers in blood and bone marrow (Haley et al., 1995, Adv. Exp. Med. Biol. 378: 289-91). For example, in the non-adherent mononuclear blood cell fraction, separated at a density of 1.077 g/ml in a density gradient, only 0.1 per million of the cells revealed staining with dendritic cell marker Ki-M4 (Parwaresch et al., 1983, Blood 62:585-90).
We have discovered that certain soluble tumor antigens, shed from tumor cells of solid, non-lymphoid tumors, are capable of inducing an immune response which promotes tumor progression (one or more of tumor growth, invasion, and metastasis). This mechanism of promotion of tumor progression involves the specific type of immune response induced by shed tumor antigen. This specific immune response, a "pro-tumor immune response", may involve (a) the contact or presence of shed tumor antigen in relation to the cell surface of B cells, such as by antigen itself or as presented by follicular dendritic cells or other antigen presenting cells; (b) activation of such B cells to proliferate, and to differentiate into plasma cells which secrete anti-shed tumor antigen antibody; and (c) formation of immune complexes, comprising anti-shed tumor antigen antibody complexed to shed tumor antigen, which may act indirectly (via immune effector cells) and/or directly (on the tumor cells) to mediate tumor progression. Also, we have developed various compositions and methods for treating a pro-tumor immune response.
Therefore, a need exists for methods which may be used to screen for the possible presence of a pro-tumor immune response in an individual; particularly in an individual who has a solid, non-lymphoid tumor, or an individual who is at high risk (e.g., environmentally and/or genetically) for developing a solid, non-lymphoid tumor, or an individual who has been treated for a solid, non-lymphoid tumor and thereby inherently carries a risk of recurrence.